Mutations of BRAF are associated with extensive hMLH1 promoter methylation in sporadic colorectal carcinomas
Mutations of BRAF are associated with extensive hMLH1 promoter methylation in sporadic colorectal carcinomas
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DOI：
10.1002/ijc.11523
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发表时间：
2004-01-10
影响因子：
6.4
通讯作者：
Mano, H
中科院分区：
文献类型：
--
作者：
Koinuma, K;Shitoh, K;Mano, H
在微卫星不稳定（MSI+）结直肠癌（CRC）中经常观察到BRAF的激活突变，其中BRAF和KRAS的突变是相互排斥的。以前，我们报道过hMLH 1的高甲基化可能在右侧散发性CRC的肿瘤发生中起重要作用，MSI显示KRAS/TP 53改变的频率较低。因此，我们假设BRAF突变可能与hMLH 1甲基化状态而不是MSI状态高度相关。本研究检测了140例结直肠癌组织中BRAF和KRAS基因突变及其与MSI和hMLH 1甲基化状态的关系。甲基化状态分为完全甲基化（FM）、部分甲基化（PM）和非甲基化（NM）3种类型。只有FM与hMLH 1蛋白表达减少密切相关。在16例（11%）病例中发现了BRAF突变，所有突变均导致BRAF（V599 E）的产生。至于MSI状态，在43%的MSI+和4%的MSI-病例中发现BRAF突变（p < 0.0001）。在MSI+个体中，BRAF突变在hMLH 1缺陷病例中（58%）比hMSH 2缺陷病例（0%; p = 0.02）更常见。此外，它们在FM、PM和NM中的检出率分别为69%、4%和4%，表明FM与其他两组之间存在显著差异（FM与PM或NM;p < 0.0001）。这些结果表明，BRAF激活可能参与了散发性CRC癌与hMLH 1高甲基化在近端结肠，独立于KRAS激活。(C)2003 Wiley-Liss，Inc.
Activating mutations of BRAF have been frequently observed in microsatellite unstable (MSI+) colorectal carcinomas (CRCs), in which mutations of BRAF and KRAS are mutually exclusive. Previously, we reported that hypermethylation of hMLH1 might play an important role in the tumorigenesis of right-sided sporadic CRCs with MSI showing less frequency of KRAS/TP53 alteration. Therefore, we have assumed that BRAF mutations might be highly associated with hMLH1 methylation status rather than MSI status. In this study, mutations of BRAF and KRAS and their relationship with MSI and hMLH1 methylation status were examined in 140 resected specimens of CRC. The methylation status was classified into 3 types: full methylation (FM), partial methylation (PM) and nonmethylation (NM). Only FM closely linked to reduced expression of hMLH1 protein. BRAF mutations were found in 16 cases (11%), all leading to the production of BRAF(V599E). As for MSI status, BRAF mutations were found in 43% of MSI+ and 4% of MSI- cases (p < 0.0001). Among the MSI+ individuals, BRAF mutations were more frequent in cases with hMLH1 deficiency (58%) than those with hMSH2 deficiency (0%; p = 0.02). Moreover, they were found in 69% of FM, 4% of PM and 4% of NM, revealing a striking difference between FM and the other 2 groups (FM vs. PM or NM;p < 0.0001). These findings suggest that BRAF activation may participate in the carcinogenesis of sporadic CRCs with hMLH1 hypermethylation in the proximal colon, independently of KRAS activation. (C) 2003 Wiley-Liss, Inc.